IGF-1-overexpressing mesenchymal stem cells accelerate bone marrow stem cell mobilization via paracrine activation of SDF-1alpha/CXCR4 signaling to promote myocardial repair.
We hypothesized that mesenchymal stem cells (MSCs) overexpressing insulin-like growth factor (IGF)-1 showed improved survival and engraftment in the infarcted heart and promoted stem cell recruitment through paracrine release of stromal cell-derived factor (SDF)-1alpha. Rat bone marrow-derived MSCs were used as nontransduced ((Norm)MSCs) or transduced with adenoviral-null vector ((Null)MSCs) or vector encoding for IGF-1 ((IGF-1)MSCs). (IGF-1)MSCs secreted higher IGF-1 until 12 days of observation (P<0.001 versus (Null)MSCs). Molecular studies revealed activation of phosphoinositide 3-kinase, Akt, and Bcl.xL and inhibition of glycogen synthase kinase 3beta besides release of SDF-1alpha in parallel with IGF-1 expression in (IGF-1)MSCs. For in vivo studies, 70 muL of DMEM without cells (group 1) or containing 1.5x10(6) (Null)MSCs (group 2) or (IGF-1)MSCs (group 3) were implanted intramyocardially in a female rat model of permanent coronary artery occlusion. One week later, immunoblot on rat heart tissue (n=4 per group) showed elevated myocardial IGF-1 and phospho-Akt in group 3 and higher survival of (IGF-1)MSCs (P<0.06 versus (Null)MSCs) (n=6 per group). SDF-1alpha was increased in group 3 animal hearts (20-fold versus group 2), with massive mobilization and homing of ckit(+), MDR1(+), CD31(+), and CD34(+) cells into the infarcted heart. Infarction size was significantly reduced in cell transplanted groups compared with the control. Confocal imaging after immunostaining for myosin heavy chain, actinin, connexin-43, and von Willebrand factor VIII showed extensive angiomyogenesis in the infarcted heart. Indices of left ventricular function, including ejection fraction and fractional shortening, were improved in group 3 as compared with group 1 (P<0.05). In conclusion, the strategy of IGF-1 transgene expression induced massive stem cell mobilization via SDF-1alpha signaling and culminated in extensive angiomyogenesis in the infarcted heart.
Haider
Husnain Kh
HKh
Department of Pathology and Laboratory of Medicine, 231 Albert Sabin Way, University of Cincinnati, Cincinnati, OH 45267-0529, USA.
Jiang
Shujia
S
Idris
Niagara M
NM
Ashraf
Muhammad
M
D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology*; D002470:Cell Survival; D054377:Chemokine CXCL12 / Q000502:physiology*; D005786:Gene Expression Regulation; D006133:Growth Substances / Q000502:physiology; D006321:Heart / Q000503:physiopathology*; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000172:deficiency / Q000235:genetics*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology*; D009203:Myocardial Infarction / Q000601:surgery / Q000628:therapy*; D051381:Rats; D055647:Rats, Transgenic; D019718:Receptors, CXCR4 / Q000502:physiology; D015398:Signal Transduction; D014945:Wound Healing / Q000502:physiology*
C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D006133:Growth Substances; D019718:Receptors, CXCR4; D007334:Insulin-Like Growth Factor I